Prostate cancer is a global health concern, which has a low survival rate in its advanced stages. Even though second-generation androgen receptor-axis inhibitors serve as the mainstay treatment options, utmost of the metastatic cases progress into castration-resistant prostate cancer after their initial treatment response with poor prognostic outcomes. Hence, there is a dire need to develop effective inhibitors that aim the causal oncogenes tangled in the prostate cancer initiation and progression. Molecular-targeted therapy against E-26 transformation-specific (ETS) transcription factors, particularly ETS-related gene, has gained wide attention as a potential treatment strategy. ETS rearrangements with the male hormone responsive transmembrane protease serine 2 promoter defines a significant number of prostate cancer cases and is responsible for cancer initiation and progression. Notably, inhibition of ETS activity has shown to reduce tumorigenesis, thus highlighting its potential as a clinical therapeutic target. In this review, we recapitulate the various targeted drug approaches, including small molecules, peptidomimetics, nucleic acids, and many others, aimed to suppress ETS activity. Several inhibitors have demonstrated ERG antagonist activity in prostate cancer, but further investigations into their molecular mechanisms and impacts on nontumor ETS-containing tissues is warranted.